Mechanism of preventive effects of exendin-4 and des-fluoro-sitagliptin in a murine model of fructose-induced prediabetes |
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| Institution: | 1. Centro de Endocrinología Experimental y Aplicada - CENEXA (UNLP-CONICET CCT LA PLATA CEAS CICPBA), Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Street 60 and 120, La Plata 1900, Argentina;2. Facultad de Ciencias Médicas, Universidad Nacional de La Plata, Street 60 and 120, La Plata 1900, Argentina;3. Instituto de Ciencias de la Salud, UNAJ-CICPBA, Street Avenue Calchaqui 6200, Florencio Varela 1888, Argentina;1. Department of Pharmacology, Vanderbilt University School of Medicine, Nashville, TN 37232, United States of America;2. Department of Chemistry, Vanderbilt University, Nashville, TN 37235, United States of America;3. Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, TN 37232, United States of America;1. Department of Medical Biotechnology and Translational Medicine, University of Milano, 20054 Segrate, Milano, Italy;2. UK Dementia Research Institute at UCL, London, UK;3. Neuro-Sys, 410 Chemin Départemental 60, 13120 Gardanne, France;4. Department of Immunology, St. Jude Children''s Research Hospital, Memphis, TN 38105, USA;5. Department of Chemistry, University of Milano, Milan, Italy;1. Department of Foundations of Medicine, NYU Long Island School of Medicine, Mineola, NY, USA;2. Department of Pediatrics, NYU Long Island School of Medicine, Mineola, New York, USA;3. Food Science Department, Rutgers Center for Lipid Research and Institute of Food Nutrition and Health, Rutgers University, New Brunswick, NJ, USA;4. Department of Obstetrics and Gynecology, NYU Long Island School of Medicine, Mineola, New York, USA;1. Pharmaceutics, Graduate School of Clinical Pharmacy, Kyushu University of Health and Welfare, 1714-1 Yoshino-machi, Nobeoka, Miyazaki 882-8508, Japan;2. Faculty of Pharmacy, Yasuda Women''s University, Hiroshima, Japan;3. Graduate School of Biomedical Sciences, Tokushima University, Tokushima, Japan;4. Faculty of Pharmaceutical Sciences, Sojo University, Kumamoto, Japan;1. School of Biological Sciences, Victoria University of Wellington, Wellington, New Zealand;2. Department of Biochemistry and Pharmacology, University of Melbourne, Parkville, Australia;3. School of Chemistry, University of Melbourne, Parkville, Australia;4. Department of Biochemistry, Albert Einstein College of Medicine, Bronx, New York, USA;5. Ferrier Research Institute, Victoria University of Wellington, Wellington, New Zealand;6. Bio21 Molecular Science & Biotechnology Institute, University of Melbourne, Parkville, Australia;1. Centre for Lipid Research, Key Laboratory of Molecular Biology for Infectious Diseases, Ministry of Education, Institute for Viral Hepatitis, Department of Infectious Diseases, the Second Affiliated Hospital, Chongqing Medical University, 400016 Chongqing, China;2. John Moorhead Research Laboratory, Centre for Nephrology, University College London Medical School, Royal Free Campus, University College London, London NW3 2PF, United Kingdom |
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| Abstract: | Protective effects of exendin-4 (glucagon-like peptide-1 -GLP-1- receptor agonist) and des-fluoro-sitagliptin (dipeptidyl peptidase-4 inhibitor) on fructose-induced hepatic disturbances were evaluated in prediabetic rats. Complementary, a possible direct effect of exendin-4 in human hepatoblastoma-derived cell line HepG2 incubated with fructose in presence/absence of exendin-9-39 (GLP-1 receptor antagonist) was investigated. In vivo, after 21 days of fructose rich diet, we determined: glycemia, insulinemia, and triglyceridemia; hepatic fructokinase, AMP-deaminase, and G-6-P dehydrogenase (G-6-P DH) activities; carbohydrate-responsive element-binding protein (ChREBP) expression; triglyceride content and lipogenic gene expression (glycerol-3-phosphate acyltransferase -GPAT-, fatty acid synthase -FAS-, sterol regulatory element-binding protein-1c -SREBP-1c); oxidative stress and inflammatory markers expression. In HepG2 cells we measured fructokinase activity and triglyceride content. Hypertriglyceridemia, hyperinsulinemia, enhanced liver fructokinase, AMP-deaminase, and G-6-P DH activities, increased ChREBP and lipogenic genes expression, enhanced triglyceride level, oxidative stress and inflammatory markers recorded in fructose fed animals, were prevented by co-administration of either exendin-4 or des-fluoro-sitagliptin. Exendin-4 prevented fructose-induced increase in fructokinase activity and triglyceride contain in HepG2 cells. These effects were blunted co-incubating with exendin-9-39. The results demonstrated for the first time that exendin-4/des-fluro-sitagliptin prevented fructose-induced endocrine-metabolic oxidative stress and inflammatory changes probably acting on the purine degradation pathway. Exendin 9–39 blunted in vitro protective exendin-4 effects, thereby suggesting a direct effect of this compound on hepatocytes through GLP-1 receptor. Direct effect on fructokinase and AMP-deaminase activities, with a key role in the pathogenesis of liver dysfunction induced by fructose, suggests purine degradation pathway constitute a potential therapeutic objective for GLP-1 receptor agonists. |
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